tbuckley/cabot-search huggingface dataset:
Impact of second primary malignancy post-autologous hematopoietic stem cell transplantation on outcomes of multiple myeloma: A CIBMTR analysis.
Authors: Brittany K. Ragon, Anita D'Souza, Noel Estrada-Merly, Raphael Fraser, Gemlyn George, Lohith Gowda, Nina Shah, Muzaffar H. Qazilbash, Shaji Kumar, Mary M. Horowitz, Saad Zafar Usmani, Mithun Vinod Shah
Journal: Journal of Clinical Oncology (2022)

8057 Background: Following autologous hematopoietic stem cell transplant (auto HCT), maintenance therapies improve survival, reduce relapse risk in multiple myeloma (MM), and are the de facto standard-of-care. However, clinical trials have shown an increased risk of second primary malignancies (SPM) with maintenance therapy, including second hematological malignancies (SHM). We examined data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to evaluate the impact of SPM on progression-free (PFS) and overall survival (OS) and the utilization of allogeneic HCT in patients with therapy-related myeloid neoplasms (t-MN). Methods: Adult patients (pts) with MM who underwent first auto HCT in the United States with a melphalan conditioning regimen from 2011-2018 and subsequently received maintenance therapy were included (N=3948). The primary endpoint of interest was the impact of SPM and SHM on OS. Multivariate analytic (MVA) modelling was applied, accounting for competing risks while integrating significant covariates to determine the impact of SPM on PFS and OS. Finally, we studied the utilization and survival following allogeneic HCT for SHM. Results: Baseline characteristics were similar between the two groups. Maintenance regimens used were lenalidomide (2836, 72%), bortezomib (370,9 %) or lenalidomide + bortezomib (372, 9%) based combinations. At a median follow up of 37 months, 175 (5%) pts developed SPM, including 112 (64%) solid 36 (21%) myeloid, and 27 (15%) lymphoid cancers. In MVA, the development of SPM and SHM was associated with an inferior PFS (HR 2.62, P&lt;0.001 and HR 5.01, P&lt;0.001, respectively) and OS (HR 3.85, P&lt;0.001 and 8.13, P&lt;0.001, respectively). The two commonest causes of death were MM (42%) and SPM (30%) for those developing SPM. Similarly, MM (53%) and SHM (18%) were the two commonest causes of death for those developing SHM. Nine (14%,5 t-MDS and 4 t-AML) of 63 patients with SHM underwent an allogeneic HCT. Patients undergoing allogeneic HCT were more likely to have Karnofsky score ≥90 (100% vs. 50%, P=0.02) compared to those who did not. One year survival from allo SCT was 66.7% (CI 34.6-92%). Conclusions: The three-year cumulative incidence of SPM was 3.3 (2.6-4)% in this large contemporaneous CIBMTR cohort. Disease relapse remains the primary cause of death in MM patients who develop SPM or SHM. Given the median OS for MM is now &gt; 10 years, longer follow-up is needed to assess the SPM and SHM risks with maintenance therapy post-auto HCT.
Evaluating the effects of critical metabolite depletion in pediatric rhabdomyosarcoma (RMS) using a novel inhibitor of nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Victor Collins, Grace McKay-Corkum, Choh Yeung, Sameer Issaq, Christine M Heske
Journal: Journal of Clinical Oncology (2022)

e22004 Background: RMS is the most common pediatric cancer of the soft tissues. Patients who present with metastatic disease or experience recurrence have a poor prognosis; survivors often suffer from long-term systemic effects resulting from cytotoxic chemotherapy. Thus, novel therapies are needed. NAMPT inhibitors are a class of drugs targeting a key metabolic enzyme in the production of NAD + , a coenzyme critical to energy generation in some cancer cells. In this study, we evaluated the mechanism and functional outcomes of treatment with the clinical NAMPT inhibitor, OT-82, in preclinical models of RMS. Methods: Live cell analysis via IncuCyte was used to determine the temporal effects of OT-82 on cell growth in a diverse panel of ten fusion positive and negative RMS cell lines. Analysis of the proposed mechanism of action was performed using NAD/NADH detection assays and rescue experiments with nicotinamide mononucleotide (NMN), the product of NAMPT. Markers of cellular apoptosis and necrosis were quantified with flow cytometric assays. Specific metabolic effects of OT-82 were determined with ATP quantification and real-time extracellular flux analysis of oxidative phosphorylation and glycolysis. In vivo studies were performed in orthotopic RMS models. Tumor dimensions were measured with calipers, and toxicity was assessed by observation and body weight measurement. Results: Treatment of RMS cell lines with OT-82 dosed in the low nanomolar range resulted in time- and dose-dependent decreases in NAD + levels and proliferation in all cell lines tested. Addition of NMN rescued cell growth, confirming the on-target activity and functional effect of OT-82. Flow cytometric assays revealed cell-line dependent differences in cell fates, with a subset of cell lines staining positive for markers of necrosis, and the other subset staining negative for markers of necrosis and apoptosis. Functional investigation verified that necrotic cell lines did not regrow after withdrawal of OT-82 in culture (durable responders), whereas non-necrotic cell lines recovered growth (transient responders). Additionally, ATP levels in durable responders decreased with OT-82 treatment but remained stable in transient responders. Extracellular flux analysis revealed that both durable and transient responders experienced inhibition of glycolysis, but that oxidative phosphorylation was only reduced in the durable responders. In vivo studies using OT-82 on a clinically-relevant schedule demonstrated that all RMS xenografts underwent complete tumor regression, with durable responder models experiencing a longer tumor-free period following discontinuation of treatment. Conclusions: In vitro and in vivo efficacy of OT-82 suggest that targeting NAD + metabolism through NAMPT inhibition may be a promising approach for the treatment of RMS.
COVID-19 Vaccination Coverage, by Race and Ethnicity — National Immunization Survey Adult COVID Module, United States, December 2020–November 2021
Authors: Jennifer L. Kriss, Mei-Chuan Hung, Anup Srivastav, Carla L. Black, Megan C. Lindley, James T. Lee, Ram Koppaka, Yuping Tsai, Peng-Jun Lu, David Yankey, Laurie D. Elam-Evans, James A. Singleton
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Some racial and ethnic minority groups have experienced disproportionately higher rates of COVID-19-related illness and mortality (1,2). Vaccination is highly effective in preventing severe COVID-19 illness and death (3), and equitable vaccination can reduce COVID-19-related disparities. CDC analyzed data from the National Immunization Survey Adult COVID Module (NIS-ACM), a random-digit-dialed cellular telephone survey of adults aged ≥18 years, to assess disparities in COVID-19 vaccination coverage by race and ethnicity among U.S. adults during December 2020-November 2021. Asian and non-Hispanic White (White) adults had the highest ≥1-dose COVID-19 vaccination coverage by the end of April 2021 (69.6% and 59.0%, respectively); ≥1-dose coverage was lower among Hispanic (47.3%), non-Hispanic Black or African American (Black) (46.3%), Native Hawaiian or other Pacific Islander (NH/OPI) (45.9%), multiple or other race (42.6%), and American Indian or Alaska Native (AI/AN) (38.7%) adults. By the end of November 2021, national ≥1-dose COVID-19 vaccination coverage was similar for Black (78.2%), Hispanic (81.3%), NH/OPI (75.7%), and White adults (78.7%); however, coverage remained lower for AI/AN (61.8%) and multiple or other race (68.0%) adults. Booster doses of COVID-19 vaccine are now recommended for all adults (4), but disparities in booster dose coverage among the fully vaccinated have become apparent (5). Tailored efforts including community partnerships and trusted sources of information could be used to increase vaccination coverage among the groups with identified persistent disparities and can help achieve vaccination equity and prevent new disparities by race and ethnicity in booster dose coverage.
Systematic definition of treatment modality and clinical outcomes reporting system in case of surgical treatment for Von Hippel-Lindau renal cell carcinoma
Authors: A. Larcher, F. Belladelli, A. Ieva, I. Rowe, G. Fallara, D. Cignoli, G. Colandrea, M. Santangelo, R. Lucianò, C. Doglioni, S. Clerici, L. Castellino, A. Damascelli, G. Guazzarotti, F. De Cobelli, R. Bertini, F. Montorsi, U. Capitanio, A. Salonia
Journal: European Urology (2022)
Amphotericin B release rate is the link between drug status in the liposomal bilayer and toxicity
Authors: Yuri Svirkin, Jaeweon Lee, Richard Marx, Seongkyu Yoon, Nelson Landrau, Md Abul Kaisar, Bin Qin, Jin H. Park, Khondoker Alam, Darby Kozak, Yan Wang, Xiaoming Xu, Jiwen Zheng, Benjamin Rivnay
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Amphotericin B (AmB) is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections. Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer, which heat treatment (curing) modifies. Although toxicity was found related to aggregation status - loose aggregates significantly more toxic than tight aggregates - the precise mechanism linking aggregation and toxicity was not well understood. This study directly measured drug release rate from various AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state, drug release, and in vitro toxicity. UV-Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features: a ∼25 nm blue-shift of the main absorption peak (λmax) in aqueous buffer and a decrease in the OD346/OD322 ratio upon thermal curing, reflecting tighter aggregation. In vitro release testing (IVRT) data showed, by applying and fitting first-order release kinetic models for one or two pools, that curing impacts two significant changes: a 3-5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated, more thermodynamically stable drug pool. The kinetic data thus corroborated the trend independently deduced from the UV-Vis spectral data. The in vitro toxicity assay indicated a decreased toxicity with curing, as shown by the significantly increased concentration, causing half-maximal potassium release (TC50). The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation. This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release (directly measured rate constants), providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.
Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial
Authors: Robert J Motzer, Thomas Powles, Mauricio Burotto, Bernard Escudier, Maria T Bourlon, Amishi Y Shah, Cristina Suárez, Alketa Hamzaj, Camillo Porta, Christopher M Hocking, Elizabeth R Kessler, Howard Gurney, Yoshihiko Tomita, Jens Bedke, Joshua Zhang, Burcin Simsek, Christian Scheffold, Andrea B Apolo, Toni K Choueiri
Journal: The Lancet Oncology (2022)
MiRNAs hsa-miR-30a-5p and hsa-miR-99b-5p regulate chemokine-mediated immune response in colorectal cancer.
Authors: Oleg I. Kit, Anton A. Pushkin, Dmitry Yu. Gvaldin, Inna A. Novikova, Natalya N. Timoshkina, Natalya V. Soldatkina, Yuriy A. Gevorkyan, Dmitriy S. Petrov, Vladimir E. Kolesnikov, Dmitriy A. Savchenko, Roman E. Tolmakh, Andrey V. Dashkov, Oksana V. Katelnitskaya, Sergei A. Ilchenko, Elena A. Dzhenkova, Evgeniy N. Kolesnikov, Aleksey Yu. Maksimov, Aleksandr V. Shaposhnikov
Journal: Journal of Clinical Oncology (2022)

e15500 Background: The immune response plays a key role in the oncogenesis of colorectal cancer. The heterogeneity of the tumor environment determines the need for immunogenetic profiling to identify associations with the implementation of tumor-specific immune responses in colorectal cancer. The purpose of our study was to describe the expression profiles of miRNAs and genes involved in the regulation of the immune response in colorectal cancer. Methods: The study included 18 patients (median age 66 years) diagnosed with colorectal cancer who were treated at the National Medical Research Centre for Oncology in 2018-2019. Total RNA was isolated using TRIzol (Thermo Fisher, USA) followed by treatment with DNase 1 (ThermoFisher, USA). Sequencing of RNA samples was performed using two approaches: AmpliSeq for Illumina Immune Response Panel (Illumina, USA) and TruSeq Small RNA Library Prep Kit -Set A (Illumina, USA) according to the manufacturer's instructions on a NextSeq 550 device (llumina, USA). Results: The study revealed 168 differentially expressed genes and 46 differentially expressed miRNAs (p &lt; 0.05). 29 miRNA-mRNA pairs were identified. It has been established that the key signaling mechanism involved in the regulation of the tumor-specific immune response is chemokine signaling pathway (hsa04062). Expression of the CXCL1 and CXCL10 genes encoding the chemokines of the same name is increased in tumor cells (logFC = 1.51, p = 0.006 and logFC = 2.67, p &lt; 0.001, respectively). At the same time, the level of hsa-miR-30a-5p and hsa-miR-99b-5p, which negatively regulate the expression of CXCL1 and CXCL10, is decreased (logFC = -2.26, p &lt; 0.001 and logFC = -1.57, p &lt; 0.001). Conclusions: Activation of expression CXCL1 and CXCL10 with simultaneous loss of negative regulators hsa-miR-30a-5p and hsa-miR-99b-5p was determined in colorectal tumors by NGS-sequencing, which seems promising for the development of personalized therapy, based on the immunogenetic features of colon tumors.
Reduced blood product utilization via implementation of an anemia clinic and consult service in a large health system hospital.
Authors: Reid Christian Bowers, Sandra Tomany Korman, Michael A. Thompson, Sherjeel Sana, Manish Krishna Pant, Federico Augusto Sanchez
Journal: Journal of Clinical Oncology (2022)

e18799 Background: An Anemia Clinic program was started Sept. 2016 as part of system wide implementation of Patient Blood Management (PBM) initiated in 2015. Methods: The Anemia Clinic accepted referrals for non-cancer anemia, predominantly preoperative cardiovascular surgery (CVS) Pts. Hgb thresholds were &lt; 13 g/dL in men and &lt; 12 g/dL in women. Non-anemia cytopenias triggered Hematology referral. All Pts were screened for iron, B12, folate, and reticulocyte count. Nutrient deficiencies were supplemented. Pts with CKD or chronic disease were considered for erythropoiesis stimulating agents. Results: PBM implementation resulted in a drop in packed red blood cell (PRBC) usage (Table). Of CVS Pts pre-operatively anemic in 2021, 169 were referred to the Anemia Clinic and 352 were not. The percentage of Pts who received PRBCs after Anemia Clinic referral was statistically different from those who were not referred (67.5% vs. 52.8% chi-square p = 0.002). Of preoperatively anemic Pts who were transfused in 2021, an average of 2.67 PRBCs were used in the referred group vs. an average of 2.36 PRBCs in those in the not referred group (negative binomial p = 0.18). Length of stay (LOS) which was a median 10d ( P 25 = 7d, P 75 = 18d) in the referred group vs a median 10d ( P 25 = 6d, P 75 = 16.5d) in the non-referred group was not statistically different between groups (Smirnov p = 0.36). LOS analyses of observed-to-expected (O/E) ratios used the Premier Healthcare Providers Alliance Database (PHD) which contains data on approximately 45% of US hospital discharges. For 2021 through Nov. the referred group had an O/E = 0.93 (observed LOS μ geo = 10.88 days, expected LOS μ geo = 11.67 days, N = 154). The not referred group had an O/E = 1.04 (observed LOS μ geo = 10.56 days, expected LOS μ geo = 10.18 days, N = 305). Conclusions: PBM decreased PRBC use through systematization of best practices during the initial year, and that decrease has persisted for six years. Subsequent addition of Anemia Clinic services did not decrease PRBC use further. A trend toward shorter LOS for patients referred to Anemia Clinic did not continue this year, but the difference in LOS from the not referred group was not statistically significant and observed LOS for the referred group was lower than expected LOS. Our methods improved nutrient deficiency identification which may improve both later health outcomes not detected here and access to treatment for hematologic malignancies.[Table: see text]
Endothelin-1 amplifies ventricular repolarization heterogeneities in chronic myocardial infarction pigs
Authors: A Olivan-Viguera, A Perez-Martinez, E Pueyo
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de Ciencia e Innovación (Spain) Diputación General de Aragón Introduction Endothelin-1 (ET-1) is a vasoconstrictor peptide secreted by endothelial cells and cardiac myocytes and fibroblasts. It is involved in oxidative stress, apoptosis regulation and ventricular remodeling processes associated with heart failure and ischemic cardiomyopathy, including myocardial hypertrophy, fibrosis and impaired conduction. ET-1 has been shown to influence cardiac electrophysiology by modulation of calcium and potassium currents and to contribute to arrhythmogenesis and sudden cardiac death. Purpose We aim to characterize the functional role of ET-1 in the electrophysiology of healed myocardial infarction (MI) by analysis of porcine ventricular slices as a highly representative model of ventricular tissue with preserved cellular cross-talks and architecture. Methods Domestic pigs (60–80 kg, n = 3) were infarcted by temporal occlusion of the left anterior descending coronary artery. 8-12 weeks after infarct induction, animals were cardioplegically arrested under deep anesthesia and sacrificed. All animal procedures conformed to the guidelines from Directive 2010/63/EU and were approved by local authorities. 350 µm-thick ventricular slices were produced from transmural tissue blocks of healed MI ventricles. Tissue blocks were taken from remote, adjacent and border zones of the infarct area. Slices were optically mapped within 8 hours after tissue collection to record transmembrane potential and intracellular calcium. Action Potential Duration (APD) and Calcium Transient Duration (CaTD) were measured at 80% repolarization for 0.5, 1 and 2 Hz pacing frequencies in the presence and absence of 100 nM ET-1. The notation n/N is used to denote n tissue slices from N pigs. Results ET-1 prolonged the APD at all frequencies in remote zones, with mean prolongation percentages of 30.5%, 32%, 26.2% at 0.5, 1 and 2 Hz, respectively, n/N=7/3. However, only minor effects were observed in adjacent (mean APD prolongation of 3.3%, 4.9% and 10.7%, n/N=5/3) and border zones (7%, 4% and 3.6%, n/N=5/3). ET-1 caused an increase in CaTD at 1 Hz in the three zones, with no significant regional differences in the amount of CaTD increase: mean prolongation of 14.1% (n/N=7/3) in the remote zone, 12.4 % (n/N=5/3) in the adjacent zone and 20.9% (n/N=4/3) in the border zone. Conclusions In chronic MI pigs, ET-1 induces strong APD and moderate CaTD prolongation of remote normal myocardium at low (0.5 Hz) to high (2 Hz) frequencies. The ET-1-induced effects on the AP of normal tissue, but not on CaT, are disrupted in the border zones of the infarct area and in its proximity. Our results point to ET-1 acting to enhance ventricular repolarization dispersion in chronic MI pigs, which might contribute to increased arrhythmia vulnerability.
MEDB-18. Elongation control of mRNA translation supports Group 3 medulloblastoma adaptation to nutrient deprivation
Authors: Alberto Delaidelli, Betty Yao, Que Xi Wang, Yue Zhou Huang, Gian Luca Negri, Christopher Hughes, Haifeng Zhang, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2022)

Abstract Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&amp;lt; 0.05).Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.